When drugs are administered for treatment, active ingredients are delivered via physiochemically designed systems to maximize the treatment effect and to suit the convenience of patients. These systems are called dosage forms which include injections, capsules and tablets.
Administered drugs pass through many biomembranes and organs to finally reach target organs. The drug reached the target organ combines with receptors distributed over the organ to realize pharmaceutical effects. After then, the drug is metabolized by liver and other organs and released out of body with stool and/or urine. The problem is, however, it is usually difficult to control the process of delivering drugs to the target area, and the efficiency of delivery is usually low. Hence, to obtain an optimal effect and safety, it is necessary to control the in vivo behavior of drugs from the moment of administration until excretion to accomplish a selective delivery to the target area by employing a variety of methods. The system of the above control is called drug delivery system which has been extensively studied. (Galenical pharmacy-pharmaceutics, Pharmaceutics subcommittee, Committee of Colleges of Pharmacy of Korea, p 483, 2000)
Some of the drug delivery systems adopt manufacturing methods taking Advantage of nano- or micro-size particles which can deliver drugs impregnated or capsulized inside the polymer by using biodegradable polymer, and of emulsifiers. The method of using emulsifier is to prepare polymeric particles by redispersing a dispersion inside an emulsifier solution wherein active ingredients and polymer are mixed and dissolved in an organic solvent. As polymers in the dispersion is hydrophobic, they can combine with the hydrophobic parts of emulsifiers resulting in formation of dispersed globular shaped particles whose sizes tend to decrease through intensive stirring or the strength of vibration. A manufacturing method using emulsifiers has been reported; doxorubicin and poly-D,L-lactic acid-co-glycolic acid (PLGA) which are anticancer agents are dissolved in methylenechloride solution to form an oil phase, which is added into the 3% of poly vinylalcohol solution under the condition of a strong vibration of ultrasound to finally prepare PLGA nanoparticles containing doxorubicin which has an average size of less than 500 nm (Tewes F et al., European Journal of Pharmaceutics and Biopharmaceutics 66:488492, 2007). However, the manufacturing methods of nonoparticles using emulsifiers have disadvantages; when ultrasound is applied, yield of nanoparticle is good but the operation cost increases because strong energy is required; and when stirring method is employed, high mechanical energy is required for the high rotational speed. Another drawback is that this method requires adjusting the speed of adding polymer-drug. Moreover, when volatile solvents having low boiling points are used, solvent recovery apparatuses are required to avoid risks involved, and the yield of nanoparticles decreases due to the extensive and/or uneven distribution of particles. To solve these problems, a process to manufacture nanoparticles having comparatively even distribution and high yield even under the low mechanical energy setting has been greatly needed.
Patients with chronic diseases are required to take poorly soluble drugs containing poorly soluble materials as active ingredients over a long period of time. This means a single intake of even a slightly heavy dose may result in side effects due to in vivo accumulation of the drug over a long period of time. With poorly soluble drugs, patients with chronic diseases should take heavy dose each time because of the low dissolution rate, which should be desperately improved to prevent side effects. In addition, to avoid inconveniences of multiple daily intakes of drugs over a long period of time, it is preferred to develop a gradually and steadily releasing dosage form which can reduce the frequency of intake and maintain a constant blood concentration over a long period of time.
For example, biphenyl-dimethyl-dicarboxylate (BDD) drugs are used to treat hepatitis and protect liver, and clinically to inhibit activities of serum transaminase, especially Serum glutamic pyruvic transaminase (SGPT) (Hyo-Seok Lee and others, The Korean Journal of Internal Medicine, vol. 40, No. 2, 1991). Animal tests have also shown that BDDs protect liver from the damage caused by toxicity of carbon tetrachloride or thioacetamide, and increase activities of cytochrome P450 2B1 mRNA and benzyloxyresorufin-O-dealkylase in addition to removing free radicals.
Above compounds, however, have so poor solubility in water (2.0-4.0 μg/ml) and low dissolution rate that their bioavailability is no more than 20-30% when taken as a form of tablet. (Kim H J et al., J Kor Pharm Sci Vol. 30, No. 2:119-125, 2000). Consequently, it is a demerit of liver treatment agents of BDDs; when they are administered as a form of tablet, heavy and continuous intakes are required due to the low in vivo dissolution rate and bioavailability.
On the other hand, extensive studies are in progress to enhance dissolubility of poorly soluble drugs via physical or chemical reformation and especially, studies on enabling oral intake of poorly soluble drugs via physical reformation of drug crystals by using the nanoparticle process are under way. (Khang K S et al., Polymer Science and Technology 13(3)342-359, 2002). In addition, a variety of experiments have been reported enhancing bioavailability and duration of drug effects by containing drugs in biodegradable polymeric particles.
For example, Korea Patent 2005-0038224, “Oral micro-emulsion composition comprising biphenyldimethyldicarboxylate and carduus marianus extract or silybin isolated therefrom,” discloses cases of better treatment effects on (chronic) liver diseases by virtue of enhanced bioavailability upon adding additives (co-surfactant, surfactant and oil) on the poorly soluble drugs to increase the dissolution rate.
Another Korea Patent 1997-0058726 discloses a water soluble protein-containing drug evenly distributed on a biodegradable polymer, a sustained release dosage form which improves excessive release in early stage of intake by coating the water soluble protein-containing drugs with drug particles or a biodegradable polymer matrix which are biocompatible and hydrophobic. But the dissolution rate and sustained release effects still fall short of expectations.
Thus, the present inventors have developed an original technology capable of manufacturing polymeric nanoparticles containing poorly soluble materials which are evenly distributed; by dissolving a poorly soluble materials in a biodegradable polymer solution which is dissolved in a non-volatile polar organic solvent especially in a highly hydrophilic organic solvent; and by coating with an emulsifier under the condition of low mechanical energy level stirring. The polymeric nanoparticles agent containing poorly soluble materials of the present invention may enhance bioavailability by increasing dissolution rate of poorly soluble drugs, and maintain a constant blood concentration over a long period of time, and reduce the dosage compared with the conventional poorly soluble drugs, thereby leading to completion of the present invention.